Chiral stationary phases based on derivatives of 4-amino-3,5-dinitrobenzoic acid

ABSTRACT

The invention describes new chiral stationary phases containing a 4-amino-3,5-dinitrobenzoic unit modified with chiral groups and spacer groups. The invention includes the process for the perparation of said stationary phases starting from 4-halogenated derivative of 3,5-dinitrobenzoic acid, chiral selectors obtainable as intermediates in the aforesaid process, and the use of the chiral stationary phases in the separation of enantiomers.

FIELD OF THE INVENTION

[0001] The present invention concerns the field of chromatographicseparations of racemic mixtures; the invention describes stationaryphases usable in said separations.

STATE OF THE ART

[0002] Different techniques are known for the separation of enantiomers.These are well known to the persons skilled in the art and include thefractional crystallization of acidic or basic racemic salts in thepresence of equivalent amounts of the chiral base or acid (M. Nogradi,“Stereochemistry, Basic Concepts & Applications”, Akademiai Kiado,Budapest, 1981, pp. 87-90; C. R. Bayley, N. A. Vaidya, Resolution ofRacemi by Diastereomeric Salt Formations, in A. N. Collins, G. N.Sheldrake, and J. Crosby (Editors), Chirality in Industry, 1992, pp.69-78), and the separation of racemi after conversion into a mixture ofdiastereoisomers. These diastereoisomers are separated by exploitingtheir various physical properties. However, once separated, for instancethrough crystallization on an achiral support, the diastereoisomers mustbe converted into the corresponding enantiomers; the process has thedisadvantage therefore of requiring additional chemical transformations(E. L. Eliel, S. H. Wilen, L. N. Meer, “Stereochemistry of OrganicCompounds”, John. Wiley & Sons, Inc., 1994, pp. 207-314).

[0003] The current methods, the so-called direct methods, for theseparation of enantiomers exclusively involve the transient formation ofthe diastereomeric species. In the main application of the directmethod, the racemic mixture or the enriched mixture is made to interactwith the chiral stationary phase (CSP) that is used in a chromatographiccolumn. The enantiomer that interacts most strongly with the chiralstationary phase has a greater retention time whereas the otherenantiomer is eluted first. Examples of chiral stationary phases includethe polymeric chiral materials, mainly the biopolymers such as, forexample, polysaccharides and proteins, and those based on synthesizedchiral organic molecules of low molecular weight bound to an achiralsupport (Pirkle, W. H. and Perrin, S. “Commercially available brush-typechiral selectors for the direct resolution of enantiomers” (in “Chiralseparation by liquid chromatography”, Ahuja, S.; Ed., ACS SymposiumSeries 471: 43-68, 1991) and by Welch, C. J. “Evaluation of chiralstationary phases design in the Pirkle laboratories”; J. Chromatogr. A666: 3-26, 1994.)

[0004] A class of stationary phases belonging to the synthesized chiralorganic molecules bound to an achiral support includes the phases whosestructure contains 3,5-dinitrobenzoyl (3,5-DNB) as a terminal group.These CSP are described in the scientific literature (J. Pirkle, J. Am.Chem. Soc. 1986, 108, 352), and in patents (U.S. Pat. No. 5,290,440),and are besides commercially available. These phases are characterizedby the presence of the 3,5-DNB group in a terminal position, which isthe unit exposed to the interaction with the analytes. They arerepresented by the general formula A:

[0005] Some specific examples of derivatives of 3,5-DNB are:(L)-N-(3,5-dinitrobenzoyl)leucine,(L)-N-(3,5-dinitrobenzoyl)phenylglycine. The 3,5-DNB group is a π-acidunit and is bound to an enantiomerically pure a-amino acid by an amidicbond. Such structure, although effective in the enantioseparation ofsome racemi, does not allow the enantioseparation of the vast number ofracemi that interact with the CSP by means of π-π type additionalinteractions or by means of hydrogen bond type interactions.

[0006] Another class of CSP that belongs to the group of stationaryphases based on synthesized chiral organic molecules bound to an achiralsupport includes the derivatives of 1,3-dicyanobenzene, represented bythe general formula B:

[0007] in which A is a chiral group bound to an aromatic ring via anitrogen atom, and B is a chlorine atom or a chiral group bound to anaromatic ring via a nitrogen atom.

[0008] These CSP are commercially available and have been described inthe scientific literature (D. Kontrec. et al, Chirality, 2000, 12,63-70) and in patents (WO00100464). They are characterized by thepresence of the units 1,3-dicyano-2,5-dichloro-benzene or1,3-dicyano-5-chloro-benzene that include two or three amino-substitutedgroups respectively. These CSP also have limitations with regard todifferent classes of separable analytes.

[0009] An increasing number of new racemic mixtures of the most variedstructures has recently been proposed for resolution into enantiomers:this is due inter alia to the increased ability of industry tosynthesize or extract new active molecules, and to the currentregulatory requirements that impose enantiomeric purity standards.

[0010] In this situation, the above-mentioned CSP, whose maindisadvantage lies in their impossibility of resolving different classesof analytes, prove increasingly less agreeable. Hence the increasinglyurgent need to prepare new CSP having high separation efficacy, andwhich are capable of resolving additional classes of analytes.

SUMMARY

[0011] The invention describes new chiral stationary phases containingchiral selectors consisting in a 4-amino-3,5-dinitrobenzoic unitmodified with chiral groups and bound to a solid support by means ofspacer groups. The invention includes the process for the preparation ofsaid stationary phases starting from 4-halogenated derivatives of3,5-dinitrobenzoic acid, chiral selectors obtainable as intermediates inthe aforesaid process, and the use of the chiral stationary phases inthe separation of enantiomers.

DESCRIPTION OF THE FIGURES

[0012]FIG. 1.a: Chemical structure of the stationary phases CSP I-CSP XI

[0013]FIG. 1.b: Chemical structure of the stationary phases CSP XI-CSPXIX

[0014]FIGS. 2a and 2 b: List of racemi tested

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention concerns chiral stationary phases (CSP)having broad separation spectrum, represented by the structure (I):

[0016] in which:

[0017] P is:

[0018] (i): a chiral group in an enantiomerically pure form, chosenbetween:

[0019] —(CH₂)_(n)NHCOCH(R¹)NH(R²) where:

[0020] n ranges from 2 to 4, R¹ is C₁-C₅ linear or branched alkyl, aryl;R² is COAr or Ar, where Ar is an aryl or alkylaryl group, optionallysubstituted with one or more groups chosen among: NO₂, CN, Cl, CH₃, OCH₃

[0021] —COCH(R¹)NH(R²) where:

[0022] R¹ and R²are defined as above;

[0023] (ii) or P is a spacer group covalently bound to a solid supportfor chromatography

[0024] Q is:

[0025] (i) a chiral group in an enantiomerically pure form, chosenamong:

[0026] —CHR¹⁰R¹¹ where:

[0027] R¹⁰ is H, C₁-C₅ linear or branched alkyl; R¹¹ is cycloalkyl,arylalkyl, aryl, optionally substituted with one or more groups chosenamong: NO₂, CN, Cl, CH₃, OCH₃.

[0028] —CH(R¹³)CONH(R¹⁴) where:

[0029] R¹³ is H, C₁-C₅ linear or branched alkyl, aryl, optionallysubstituted with NO_(2,) CN, Cl, CH₃, OCH₃; R¹⁴ is alkylaryl, aryl,optionally substituted with one or more groups chosen among: NO₂, CN,Cl, CH₃, OCH₃.

[0030] —CH(R³)CH(R⁴)(NHR⁵) where:

[0031] R³ and R⁴ independently of each other are C₁-C₅ linear orbranched alkyl, aryl, alkylaryl, optionally substituted with NO₂, CN,Cl, CH₃, OCH₃, or R³ forms, with R⁴ and with the carbon atoms bound toR³ and R⁴, a 5-6 term ring; R⁵ is an aryl, benzoyl group, optionallysubstituted with one or more groups chosen among: NO₂, CN, Cl, CH₃,OCH₃.

[0032] —CH[CH(R¹⁷)(R⁷)][R⁹] where:

[0033] R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH, R⁷ is H, C₁-C₅linear or branched alkyl, or R⁷ forms with R⁸ and with the carbon atomsbound to R⁷ and R⁸ a 5-6 term ring; R⁸ is H, C₁-C₅ linear or branchedalkyl, phenyl, or R⁸ forms with R⁶ and with the carbon atoms bound to R⁸and R⁵ a 5-6 term ring optionally of aromatic nature; R⁶ is H, C₁-C₅linear or branched alkyl, hydroxyl;

[0034] (ii) or Q is a spacer group covalently bound to a solid supportfor chromatography, and in which, the aforesaid formula (I) alwayscontains one chiral group and one spacer group bound to a solid support,defined as above.

[0035] Preferably the chiral group is represented by P and the spacergroup is represented by Q.

[0036] The aforesaid chiral groups (whether P or Q) always have anasymmetrical carbon atom in (R) or (S) form.

[0037] In the formula (I), the alkylaryl group is preferably representedby the benzyl group; the aryl group is preferably represented by phenyl,naphthyl, 2,5,6-trichloro-1,3-dicyanophenyl or4,5,6-trichloro-1,3-dicyanophenyl.

[0038] Within formula (I) it is possible to identify five subgroups ofchiral stationary phases particularly useful for the purpose of thepresent invention.

[0039] (a) A first group of preferred chiral stationary phases isrepresented by the formula (I) where:

[0040] P is —(CH₂)_(n)NHCOCH(R¹)NH(R²), n is 2; R¹ is methyl, isopropyl,isobutyl, phenyl, benzyl; R² is 3,5-dinitrobenzoyl,2,5,6-trichloro-1,3-dicyanophenyl, 4,5,6-trichloro-1,3-dicyanophenyl.

[0041] (b) A second group of preferred chiral stationary phases isrepresented by the formula (I) where:

[0042] Q is —CHR¹⁰R¹¹, R¹⁰ is methyl; R¹¹ is cyclohexyl, phenyl,naphthyl, anthranyl, 2,5,6-trichloro-1,3-dicyanophenyl,4,5,6-frichloro,1,3-dicyanophenyl, para-nitrophenyl;

[0043] (c) A third group of preferred chiral stationary phases isrepresented by the formula (I) where:

[0044] Q is —CH(R¹³)CONH(R¹⁴), R¹³ is methyl, phenyl, isobutyl; R¹⁴ isphenyl, dimethylphenyl;

[0045] (d) A fourth group of preferred chiral stationary phases isrepresented by the formula (I) where:

[0046] Q is —CH(R³)CH(R⁴)(NHR⁵), R³ and R⁴ are phenyl or R³ forms withR⁴ and with the carbon atoms bound to R³ and R⁴ a 6-term ring; R⁵ is4,5,6-trichloro-1,3-dicyanophenyl, 2,4,6-trichloro-1,3-dicyanophenyl;

[0047] (e) A fifth group of preferred chiral stationary phases isrepresented by the formula (I) where:

[0048] Q is CH[CH(R¹⁷)(R⁷)][R⁹] where:

[0049] R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH; R⁷ is H, or R⁷ formswith R⁸ and with the carbon atoms bound to R⁷ and R⁸ a 5-term ring, orR⁸ is H, methyl, phenyl, or R⁸ forms with R⁶ and with the carbon atomsbound to R⁶ a 5-6 term ring of aromatic nature, R⁵ is methyl, hydroxyl.

[0050] Among the aforesaid groups (a)-(e), group (a) is the mostpreferred.

[0051] The spacer group covalently bound to a solid support forchromatography preferably has the formula —(CH₂)_(n)—Si—(R¹²)(R¹⁶)—O—R¹⁵where n ranges from 1 to 10; R¹² and R¹⁶ are C₁-C₄ alkyl, C₁-C₄ alkoxy,O—R¹⁵, where R¹⁵ represents the solid support for chromatography; thespacer groups are therefore bound to the solid support by mono ormultifunctional covalent bonds.

[0052] The preferred spacer groups are those where R¹² is equal to R¹⁶and represents ethoxy, n is 3, and R¹⁵ is a silyl group of silica, orthose where R¹² is ethoxy and R¹⁶ is —OR¹⁵, and R¹⁵ is a silyl group ofsilica.

[0053] The solid support is a support suitable for use inchromatographic separations and is preferably of inorganic nature. Thesolid supports for chromatography generally contain hydroxylic groups orother oxygenated groups that are known to form covalent bonds withfunctional groups thus obtaining functionalized supports. Therefore, thesolid support is bound to the rest of the molecule of formula (I) by acovalent type bond that involves one among the aforesaidhydroxylated/oxygenated groups of the support. Examples of inorganicsolid support are silica, silica gel, alumina, kaolin, titanium oxide,magnesium oxide, silicates, synthetic polymers.

[0054] An additional object of the present invention is a productionprocess of the chiral stationary phases of formula (I).

[0055] Such process includes the following steps, applicable in anyorder:

[0056] introduction of a chiral group (P or Q) on the ring of a4-halo-3,5-dinitro-benzoic acid;

[0057] introduction of a spacer group (Q or P) on the ring of the4-halo-3,5-dinitrobenzoic acid;

[0058] formation of a covalent bond between the spacer group and thesolid support.

[0059] When a chiral group is introduced in the aforesaid steps, themeaning of P or Q is chosen among those described with (i) in theformula (I); when a spacer group is introduced, the meaning of P or Q isthat described with (ii) in the formula (I): preferably, the meaning ofP is chosen among those denoted by (i), while the meaning of Q is thatdescribed with (ii).

[0060] In a more specific and preferred embodiment of the presentprocess, the spacer group is first made to react with the solid supportand then, once bonded to the solid support, with4-halo-3,5-dinitro-benzoic acid;

[0061] The following is a first exemplification of this embodiment:

[0062] A. Introduction of a chiral group (P or Q) on the ring of the4-halo-3,5-dinitro-benzoic acid, with formation of the aminic derivative(where P substitutes the halogen in position 4 of the benzoic ring), orwith formation of the benzamidic derivative (where Q reacts with thecarboxylic function of the aforesaid acid);

[0063] B. formation of the covalent bond between the spacer group andthe solid support;

[0064] C. covalent bond between the spacer group bound to the solidsupport as obtained in step B., and the chiral selector obtained in stepA, said bond being made on position 4 of the benzoic ring or on thecarboxylic function, depending on which position has not reacted withthe chiral group; this step allows the attainment of the chiralstationary phase.

[0065] This is the preferred way of synthesis for the compounds offormula (I) in which the chiral group is the group Q, and the spacergroup is the group P.

[0066] In a second exemplification, the process includes the followingsteps:

[0067] A. formation of the covalent bond between the spacer group andthe solid support;

[0068] B. covalent bond of the spacer group (bound to the solid supportas obtained in step A) on the 4-halo-3,5-dinitro-benzoic acid with theformation of the corresponding aminic derivative (where the spacer groupsubstitutes the halogen in position 4 of the benzoic ring) or of thebenzamidic derivative (where the spacer group reacts with the carboxylicfunction of the aforesaid acid);

[0069] C. introduction of a chiral group (P or Q) on the4-halo-3,5-dinitro-benzoic acid modified in step B., on position 4 ofthe benzoic ring or on the carboxylic function, depending on whichposition has not reacted with the spacer group; this step allows theformation of the chiral stationary phase.

[0070] This is the preferred way of synthesis for the compounds offormula (I) in which the chiral group is group P and the spacer group isgroup Q.

[0071] The starting reagent used for this process is a4-halo-3,5-dinitro-benzoic acid, in which the halogen in position 4 actsas a leaving group for subsequent reactions of nucleophilicsubstitution; a preferred example of such reagent is4-chloro-3,5-dinitro-benzoic acid, commercially available.

[0072] The introduction of the groups P and Q (whether chiral or spacer)is carried out by reacting 4-halo-3,5-dinitro-benzoic acid with acompound of formula P—NH₂ or formula Q-NH₂ (where P and Q have themeanings indicated in formula (I), including the desired stereochemicalconfiguration, when P or Q represent chiral groups). The reagent P—NH₂substitutes the halogen of the 4-halo-3,5-dinitro-benzoic acid with theformation of the corresponding 4-aminic derivative (formula (Ia)). Thereagent Q-NH₂ reacts with the carboxylic function of the4-halo-3,5-dinitro-benzoic acid, leading to the formation of thecorresponding benzamidic derivative (formula (Ib)). The formulas (Ia)and (Ib) are represented below:

[0073] in the formula (Ia), P is:

[0074] (i): a chiral group in an enantiomerically pure form, chosenbetween:

[0075] —(CH₂)_(n)NHCOCH(R¹)NH(R²) where:

[0076] n ragnes form 2 to 4, R¹is C₁-C₅ linear or branched alkyl, aryl;R² is COAr or Ar, where Ar is an aryl or alkylaryl group, optionallysubstituted with one or more groups chosen among: NO₂, CN, Cl, CH₃, OCH₃

[0077] —COCH(R¹)NH(R²) where:

[0078] R¹ and R² are defined as above;

[0079] (ii) or P is a spacer group, optionally covalently bound to asolid support for chromatography

[0080] In the formula (Ib),

[0081] Hal is halogen,

[0082] Q is:

[0083] (i) a chiral group in an enantiomerically pure form, chosenamong:

[0084] —CHR¹⁰R¹¹ where:

[0085] R¹⁰ is H, C₁-C₅ linear or branched alkyl; R¹¹ is cycloalkyl,arylalkyl, aryl, optionally substituted with one or more groups chosenamong: NO₂, CN, Cl, CH₃, OCH₃.

[0086] —CH(R¹³)CONH(R¹⁴) where:

[0087] R¹³ is H, C₁-C₅ linear or branched alkyl, aryl, optionallysubstituted with NO₂, CN, Cl, CH₃, OCH₃; R¹⁴ is alkylaryl, aryl,optionally substituted with one or more groups chosen among: NO₂, CN,Cl, CH₃, OCH₃.

[0088] —CH(R³)CH(R⁴)(NHR⁵) where:

[0089] R³ and R⁴ independently of each other are C₁-C₅ linear orbranched alkyl, aryl, alkylaryl, optionally substituted with NO₂, CN,Cl, CH₃, OCH₃, or R³ forms with R⁴ and with the carbon atoms bound to R³and R⁴ a 5-6 term ring; R⁵ is an aryl, benzoyl group, optionallysubstituted with one or more groups chosen among: NO₂, CN, Cl, CH₃,OCH₃.

[0090] —CH[CH(R¹⁷)(R⁷)][R⁹] where:

[0091] R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH; R⁷ is H, C₁-C₅linear or branched alkyl, or R⁷forms with R⁸ and with the carbon atomsbound to R⁷ and R⁸ a 5-6 term ring; R₈ is H, C₁-C₅ linear or branchedalkyl, phenyl, or R⁸ forms with R⁶ and with the carbon atoms bound to R⁸and R⁶ a 5-6 term ring optionally of aromatic nature; R⁶ is H, C₁-C₅linear or branched alkyl, hydroxyl;

[0092] (ii) or Q is a spacer group, optionally covalently bound to asolid support for chromatography.

[0093] In the formula (Ia) or (Ib) the spacer group optionally bound toa solid support for chromatography preferably has theformula—(CH₂)_(n)—Si—(R¹²)(R¹⁶)—O—R¹⁵, where n ranges from 1 to 10; R¹²and R¹⁶ are C₁-C₄ alkyl, C₁-C₄ alkoxy, O—R¹⁵, R¹⁵═R¹², or R¹⁵═R¹⁶, orR¹⁵═R¹²═R¹⁶, or (in the case in which the spacer group is covalentlybonded to the solid support), R¹⁵ represents the solid support. Examplesof reagents that can be used to introduce the Q and P groups are α-aminoacids. α-arylalkylamines, amides of carboxylic acid, amino alcohols,arylamines, alkylamines, arylalkylamines. Examples of specific reagentsare: 1-phenylethylamine, proline, (I-(naphthyl-1-yl)ethylamine,phenylalanine, phenylglycine, n-butylamine, 3,5- dimethylaniline,cyclohexylethylamine, sarcosine, asparagine.

[0094] When P or Q represent the spacer group, the reagent used has theformula H₂N—(CH₂)_(n)—Si—(R¹²)(R¹⁶)—O—R¹⁵, where n ranges form 1 to 10;R¹² and R¹⁶ are C₁-C₄ alkyl, C₁-C₄ alkoxy, O—R¹⁵, R¹⁵═R¹², or R¹⁵═R¹⁶,or R¹⁵═R¹²═R¹⁶, or (in the case in which the spacer group is alreadycovalently bonded to the solid support) R¹⁵ represents the solidsupport. In the latter case, an example of an effective reagent isNucleosil 100-5-NH₂ (“silica packings with chemically bonded NH₂ polargroups” supplied by Macherey Nagel).

[0095] The introduction of the P or Q groups (whether chiral or spacer)is carried out by heating the reagents P—NH₂ or Q-NH₂ in suitablesolvents or in their mixtures, optionally in the presence of an excessof solvent. The operational temperature is between 20° C. and 120° C.and the reaction time is between 60 minutes and 80 hours. The preferredtemperature interval is 20°-70° C. and the preferred reaction timeinterval is 2-16 hours.

[0096] The bond between the spacer group and the solid support isobtained according to known chemical reactions that include heating tohigh temperatures in the presence of a solvent or mixtures of organicsolvents. The preferred conditions envisage the use of toluene, thereaction time is longer than 6 hours, preferably 16 hours, the reactiontemperature is higher than 30° C., the reaction preferably takes placeunder reflux conditions.

[0097] A class of interesting compounds for the purposes of theinvention is represented by the compounds of formula (Ia) or (Ib) inwhich the group P (formula (Ia)) or Q (formula (Ib)) is a chiral groupas defined above. Such compounds, here defined as “chiral selectors”,are new and have a specific function both as intermediates in thesynthesis of the CSP, as well as functioning, inside the CSP, as anelement of enantiomeric discrimination.

[0098] Such chiral selectors represent an additional object of theinvention and are therefore defined by the structural formula (Ia)

[0099] in which:

[0100] P is chosen between:

[0101] a chiral group in an enantiomerically pure form, chosen between:

[0102] —(CH₂)_(n)NHCOCH(R¹)NH(R²) where:

[0103] n ranges from 2 to 4, R¹ is C₁-C₅ linear or branched alkyl, aryl;R² is COAr or Ar, where Ar is an aryl or alkylaryl group, optionallysubstituted with one or more groups chosen among: NO₂, CN, Cl, CH₃, OCH₃

[0104] —COCH(R¹)NH(R²) where:

[0105] R¹ and R² are defined as above;

[0106] or by the structural formula (Ib),

[0107] in which

[0108] Hal is halogen,

[0109] Q is chosen among a chiral group in an enantiomerically pureform, of formula:

[0110] —CHR¹⁰R¹¹ where:

[0111] R¹⁰ is H, C₁-C₅ linear or branched alkyl; Rat is cycloalkyl,arylalkyl, aryl, optionally substituted with one or more groups chosenamong: NO₂, CN, Cl, CH₃, OCH₃.

[0112] —CH(R13)CONH(R¹⁴) where:

[0113] R¹³ is H, C₁-C₅ linear or branched alkyl, aryl, optionallysubstituted with NO₂, CN, Cl, CH₃, OCH₃, R¹⁴ is alkylaryl, aryl,optionally substituted with one or more groups chosen among: NO₂, CN,Cl, CH₃, OCH₃.

[0114] —CH(R³)CH(R⁴)(NHR⁵) where:

[0115] R³ and R⁴ independently of each other are C₁-C₅ linear orbranched alkyl, aryl, alkylaryl, optionally substituted with NO₂, CN,Cl, CH₃, OCH₃, or R³ forms with R⁴ and with the carbon atoms bound to R³and R⁴ a 5-6 term ring; R⁵ is an aryl, benzoyl group, optionallysubstituted with one or more groups chosen among: NO₂, CN, Cl, CH₃,OCH₃.

[0116] CH[CH(R¹⁷)(R⁷)][R⁹] where:

[0117] R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH; R⁷ is H, C₁-C₅linear or branched alkyl, or R⁷forms with R⁸ and with the carbon atomsbound to R⁷ and R⁸ a 5-6 term ring; R⁸ is H, C₁-C₅ linear or branchedalkyl, phenyl, or R⁸ forms with R⁶ and with the carbon atoms bound to R⁸and R⁶ a 5-6 term ring optionally of aromatic nature; R⁶ is H, C₁-C₅linear or branched alkyl, hydroxyl.

[0118] Within the formulas (Ia) or (Ib) it is possible to identify fivesubgroups of preferred selectors in which P or Q respectively have themeanings already mentioned above in the subgroups (a)-(e), in theformula (I): particularly preferred are the selectors of formula (Ia),where P has the aforesaid meaning for the subgroup (a), in the formula(I).

[0119] Examples of preferred selectors are listed below. The names inbrackets refer to the corresponding chiral stationary phases (CSP) whosestructures are shown in FIG. 1.

[0120] N-(1R)-(1-phenylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide(CSP I).

[0121] N-(1R)-(1-Naphthylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide(CSP JI).

[0122] N-(1R)-(9-Anthranylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide(CSP III).

[0123]N-(1R)-(1-Cyclohexylethyl)(4-chloro-3,5-dinitrophenyI)carboxyamide (CSPIV)

[0124]N-(1R)-[1-(4-Nitrophenyl)ethyl](4-chloro-3,5-dinitrophenyl)carboxyamide(CSP V)

[0125](2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]propanamide (CSP VI)

[0126](2R)-N-(3,5-Dimethylphenyl)2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-2-phenylacetamide(CSP VII)

[0127](2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-2-isobutylacetamide(CSP VIII)

[0128] N-[(1R,2R)-2-[(3,5,6-Trichloro)-2,4-dicyanophenyl)amino]cyclohexyl}-4-chloro-3,5-dinitrophenyl)carboxyamide(CSP XII)

[0129] N-[(1R,2R)-2-(2,3,5-Trichloro)-4,6-dicyanoaniline)-1,2-diphenylethyl]-4-chloro-3,5-dinitrobenzamide (CSPXIII)

[0130] N-((2S,1R)-2-Hydroxy-indanyl)-(4-chloro-3,5dinitrophenyl)carboxyamide (CSPXIV).

[0131]N-((1R)-1-Ethyl-2-hydroxyethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide(CSP XV).

[0132]N-[(1R)-2-Hydroxy-1-(methyl)ethyl](4-chloro-3,5dinitrophenyl)carboxyamide(CSP XVI)

[0133] N-((1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide (CSP XIX)

[0134] N-[(1R,2R)-2-[(4-chloro)-3,5-dinitrobenzoyl)amino]cyclohexyl}-4-chloro-3,5-dinitrophenyl)carboxyamide(CSPXX)

[0135] The stationary phases described herein allow the separation ofdifferent racemic mixtures of commercial and industrial interest. Theuse of these chiral stationary phases for enantiomeric separation bychromatography, and in particular their use in the preparation ofcolumns for liquid chromatography constitutes an additional aspect ofthe present invention. The term. liquid chromatography includesdifferent types of chromatography such as, for instance, highperformance liquid chromatography (HPLC), batch chromatography, flashchromatography, thin layer chromatography, “simulating moving bedchromatography (SMBC), supercritical fluid chromatography (SCFC).Moreover, the present invention includes a separation method ofenantiomeric mixtures through the use of said chiral stationary phases.

[0136] The present invention allows the analytical and preparativeseparation of classes of enantiomers having different chemicalstructures. In addition, it allows the determination of the enantiomericcomposition of a given mixture, obtained for example with asymmetricalsynthesis.

[0137] The separation process takes place through different effectiveinteractions that occur between the chiral selector and the enantiomer.

[0138] According to the present invention the problem of theineffectiveness or the limited efficiency in the separation of classesof racemi that is frequently found with the commercially available CSPis solved by the specific chemical structure of the new selectors of theinvention. Without wishing to be bound by theory, the functionaladvantages of the present selectors compared to known ones appear to bedue to the aromatic unit 3,5-dinitrobenzene (strong π-acid unit)interposed between the chiral group and spacer group, and where thechiral information is bound to the π-acid aromatic unit either via theamidic group in position 1 of the aromatic ring or via the amino grouppresent on position 4 of the same ring. In a particular embodiment ofthe invention, these structures include a specific organization ofπ-acid and π-basic units (among which for example 1,3-dicyanobenzene,dimethylphenyl group), known also as π-acceptor and π-donor units, thatare separated by a chiral unit so as to provide the optimum interactionwith the enantiomer of the mixture. In this context, theenantioselectivity denotes a specific interaction between the chiralselector and the enantiomer to be separated, for example a situationwhere an enantiomer with strong (hetero)aromatic properties, has a groupthat interacts with the extended aromatic unit present in the chiralselector, and also contains additional functional groups to interactwith other specific groups of the chiral selector.

[0139] The CSP object of the invention allow the separation of a widenumber of racemic analytes which are not completely or are onlypartially separated by the CSP known to the state of the art.

[0140] The separation process of enantiomers according to the inventionhas the additional advantage of allowing the separation of numerousenantiomers without the need to derivatize them. In particular, theenantiomers that are separated are mono- and polycyclic aromatic andheteroaromatic compounds optionally containing other functional groups,such as for instance hydroxy, alkoxy, alkylthio, carboxy, carboxyalkyl,amino, alkylamino, phosphine, and phosphineoxide groups, polycyclicaromatic compounds and heteroaromatic compounds containing nitrogen,sulphur, or oxygen. The expression “heteroaromatic compounds containingnitrogen, sulphur or oxygen” includes those systems having aheterocyclic ring that contains at least one atom of nitrogen, sulphur,oxygen on the aromatic ring or on the alicyclic ring condensed to thearomatic ring or on both. This expression therefore includes saturatedand unsaturated heterocycles in addition to heteroaromatic rings. Allthese compounds have an absolute configuration (R) or (S) and when theyare prepared in the absence of a chiral intervention, such as forinstance a chiral catalyst, a chiral biocatalyst, or a chiral auxiliaryagent in a stechiometric amount, they are obtained in racemic form, thatmust inevitably be separated into the single enantiomers.

[0141] Specific separation examples of racemi by means of the stationaryphases of the invention are contained in the experimental part.Particular attention is given to the separation of groups of racemi ofindustrial and commercial interest, such as for instance the derivativesof amino acids, of benzodiazepine, of dihydrodiazine among which forexample dihydropyrimidine, derivatives of binaphthyl, phosphineoxides.The following examples illustrate the invention, in a non-limitingcapacity.

Experimental Part EXAMPLE 1N-7(1R)-(1-Phenylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide

[0142] To the solution of 4-chloro-3,5-dinitrobenzoic acid (1.00 g, 4.1mmol) in dichloromethane (30 ml), dicyclohexylcarbodiimide (DCC, 0.84 g,4.1 mmol) in dichloromethane (10 ml) is added. To this solution is added(R)-(+)-1-phenylethylamine (0.49 g, 4.1 mmol) in dichloromethane (10ml). After 16 h of mixing at room temperature, the dicyclohexylurea isrecovered on a filter, the filtrate is dry evaporated. 1.40 g (98%) ofyellow powder are obtained, mp 202-203° C.

[0143] IR (KBr): 3340, 3280, 3090, 3080, 3040, 2980, 940, 2880, 1690,1610, 1250, 1200, 1450, 1350, 1290, 1130, 1060, 1010, 920, 830, 760,740, 720, 700 cm⁻¹. ¹H-NMR (CDCl₃): 1.63 (3H, d, J=7.0 Hz), 5.28 (1H,dt, J=7.2, 7.0 Hz), 7.30-7.54 (5H, m), 8.96 (2H, s) and 9.47 (1H, d,J=7.8 Hz) ppm. ¹³C-NMR (CDCl₃): 21.96, 49.38, 121.32, 126.19, 126.94,127.38, 128.35, 135.06, 143.88, 148.79, 160.86 ppm. Anal. elem.calculated for: C₁₂H₁₂O₅N₃Cl (mw 349.72): C, 51.51; H, 3.45; N, 12.01%.Found: C, 52.01; H, 3.62; N, 11.89%.

EXAMPLE 2N-(1R)-(1-Naphthylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide

[0144] The method described in Example 1 is applied and the same molaramounts of reagents are used with the difference that(R)-(+)-naphthyl-ethyl-amine (0.70 g, 4.1 mmol) is used (instead ofphenylethylamine) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline(EEDQ) is used (instead of DCC, 1.00 g, 4.1 mmol), acylation is carriedout by applying the same conditions of Example 1. The product isrecovered on a G-4 filter, washed with dichloromethane and dried. 1.55 g(95%) of yellow powder are obtained, mp 127-130° C.

[0145] IR(KBr): 3600, 3380, 3230, 3120, 1790, 1700, 1600, 1495, 1210,1070, 950, 930, 890 and 870 cm⁻¹. ¹H-NMR (DMSO-d₆): 1.65 (3H, d, J=6.64Hz), 5.92-5.99 (1H, m), 7.33-8.76 (7H, m), 8.88 (2H, s), 9.53 (1H, d,J=7.31 Hz) ppm. ¹³C-NMR (DMSO-d₆): 21.26, 45.58, 122.81, 123.03, 125.55,125.72, 126.41, 126.90, 127.42, 127.62, 128.78, 130.44, 133.45, 124.86,139.38, 148.78, 160.89 ppm. Anal. elem. calculated for:

[0146] C₁₉H₁₄O₅N₃Cl (mw 399.77): C, 57.08; H, 3.52; N, 10.51%. Found: C,57.21; H, 3.68; N, 10.06%.

EXAMPLE 3N-(1R)-(9-Anthranylethyl)(4-chloro-3,5dinitrophenyl)carboxyamide

[0147] The method described in Example 1 is applied, with the differencethat (R)-(+)-anthranylethylamine (1.01 g, 4.1 mmol) rather thanphenylethylamine is used. The product is isolated after evaporation anddrying at 70° C. for 4 h. 1.18 g (64%) of product in the form of ayellow powder are obtained, mp 283-285° C.

[0148] IR KBr): 3280, 3060, 1680. 1540, 1345, 1325, 1070, 900, and 744cm⁻¹. ¹H-NMR (DMSO-d₆): 2.05 (3H, d, J=7.0 Hz), 6.59-6.69 (1H, m),7.57-7.71 (4H, m), 8.20 (2H, d, J=8.0 Hz), 8.65 (1H, s), 8.83 (2H, d,J=8.0 Hz), 8.91 (2H, s), 10.02 (1H, s) ppm. ¹³C -NMR (DMSO-d₆): 20.84,46.60, 121.61, 124.61, 124.99, 125.86, 127.49, 128.57, 129.53, 131.46,134.76, 135.24, 148.83, ppm. Anal. elem. calculated for: C₂₃H₁₆O₅N₃Cl(mw 449.86): C, 61.41; H, 3.59; N, 9.34%. Found: C, 61.23; H, 3.63; N9.33%.

EXAMPLE 4N-(1R)-(1-Cyclohexylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide andN-(1R)-[1-(4-Nitrophenyl)ethyl](4-chloro-3,5-dinitrophenyl)carboxyamide

[0149] These selectors are prepared with the method described in Example1, with the difference that (1R-1-cyclohexylethyl-amine or(1R)-1-(4-nitrophenyl)ethyl-amine is used.

EXAMPLE 5 (2R)-2-Amino-N-(3,5-dimethylphenyl)propanamide

[0150] This compound is an intermediate for the synthesis of thecompound of example 6. To the solution of N-Boc-L-alanine (1.000 g, 5.28mmol) in dichloromethane (10 ml) is added dicyclohexylcarbodiimide (DCC,1,094 g, 5.28 mmol) in dichloromethane (10 ml). To this mixture is added3,5-dimethylaniline (0.640 g, 5.28 mmol) in dichloromethane (10 ml).After 16 h of mixing at room temperature, the dicyclohexylurea isrecovered on a filter, the filtrate is dry evaporated. 1.41 g (91%) ofwhite powder are obtained, mp 134°-136° C. The material is dissolved intrifluoroacetic acid (5 ml) and the solution is mixed for 30 min. atroom temperature. The solution is dry evaporated. The product isdissolved in methanol (10 ml). To this solution dichloromethane (30 ml)is added and the solution is washed with a solution of 1 M (30 ml)sodium carbonate and water (2×30 ml). The organic phase is dryevaporated. 0.64 g (63%) of product are obtained in the form of a brownoil.

[0151] IR(KBr): 2980, 1720, 1220, 1450, 1400, 1370, 1250, 1160, 1070,1020, 910, 860 and 830 cm⁻¹. ¹H-NMR (CDCl₃): 1.38 (3H, d, J=7.1 Hz),1.62 (2H, bs), 2.28 (6H, s), 3.56 (1 H, q, J=7.1 Hz), 6.73 (1 H, s),7.23 (2H, s), 9.39 (1 H, bs). ¹³C-NMR (CDCl₃): 20.97, 21.22, 50.87,116.96, 125.54, 137.49, 138.42, 173.81 ppm. Anal. elem. calculated for:C₁₁H₁₆ON₂ (mw 192.25): C, 68.71; H, 8.38; N, 14.57%. Found: C, 68.79; H,8.51; N, 14.53%.

EXAMPLE 6(2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]propanamide

[0152] To the solution of 4-chloro-3,5-dinitrobenzoic acid (1.058 g,4.29 mmol) and EEDQ (1.062 9, 4.29 mmol) in dichloromethane (25 ml) isadded (2R)-2-amino-N-(3,5-dimethylphenyl)propanamide, prepared inExample 5 (0.825 g, 4.29 mmol) in dichloromethane (25 ml). After 16 h ofmixing at room temperature the product is recovered on a G-4 filter andwashed with dichloromethane (30 ml). The product is dried at 50° C. for4 h. 1.026 g (56%) of yellowish powder are obtained, mp 202°-204° C.

[0153] IR(KBr): 3280, 3060, 1630, 1600, 1230, 1140, 1040, 970, 910, 800and 770 cm⁻¹. ¹H-NMR (CDCl₃): 1.76 (3H, d, J=7.0 Hz), 2.50 (6H, s), 4.92(1H, m), 6.95 (1H, s), 7.53 (2H, s), 9.04 (2H, s), 9.59 (1H, d, J=6.8Hz), 10.30 (1H, s) ppm. ¹³C-NMR (CDCl₃): 17.80, 21.20, 50.63, 117.28,121.71, 127.39, 127.64, 128.46, 128.73, 130.82, 149.36, 161.73, 163.62ppm. Anal. elem. calculated for: C₁₈H₁₇O₆N₄Cl (mw 420.79): C, 51.37; H,4.07; N, 13.31%. Found: C, 51.42; H, 4.12; N, 13.28%.

EXAMPLE 7(2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-2-isobutylacetamideand(2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5dinitrophenyi)carbonylamino]-2-phenylacetamide

[0154] These chiral selectors are prepared from L-leucine orD-phenylglycine according to Examples 5 and 6.

EXAMPLE 8 4-{[((1R,2R)-2-Aminocyclohexyl]amino}-2,5,6-trichloro-1,3-dicyanobenzene

[0155] To the suspension of 2,4,5,6-tetrachloro-1,3-dicyanobenzene (2.0g, 7.52 mmol) and triethylamine (5 ml) in methyl cyanide (40 ml) isadded a solution of (1R,2R)-diaminocyclohexane (0.85 g, 7.52 mmol) inmethyl cyanide (10 ml). The mixture is mixed for 60 min. at 120° C.,then cooled to room temperature and the water (10 ml) is slowly added.After cooling in a refrigerator the solid is recovered on a G4 filterand washed with water-methyl cyanide (1:1) and with methyl cyanide.Finally, the product is vacuum-dried on KOH tablets. 2.32 g (89%) ofpale yellow powder are obtained, dec. at a temp. greater than 190° C.

[0156] IR (KBr): 3340, 3300, 3120, 2960, 2920, 2860, 2220, 1600, 1280,1480, 1450, 1400, 1360, 1350, 1270, 1240, 1220, 1190, 1100, 1070, 1040,990, 930, 900, 870, 850, 840, 740, 730 and 610 cm⁻¹. ¹H NMR (CF₃COOD):1.16-2.25 (8H, m), 3.45 (1H, m) and 4.37 (1H, m) ppm. ¹³C NMR (CF₃COOD):22.26, 29.04, 32.58, 55.26, 57.12, 96.12, 104.96, 110.54, 112.77,122.43, 141.53, 142.47, 120.57 ppm. Anal. elem. calculated for:C₁₄H₁₃N₄Cl₃ (mw 343.63): C, 48.93%; H, 3.81%; and N, 16.30%. Found: C,48.77%; H, 4.01%; the N, 16.35%.

EXAMPLE 9 N-[(1R,2R)-2-[(3,5,6-Trichloro)-2,4-dicyanophenyl)amino]cyclohexyl}-4-chloro-3,5-dinitrophenyl)carboxyamide

[0157] The solution of 4-chloro-3,5-dinitrobenzoic acid (0.72 9, 2.90mmol) and EEDQ (0.72 g, 2.90 mmol) in dichloromethane (20 ml) is mixedfor 60 min. at room temperature, then is added4-{[(1R,2R)-2-aminocyclohexyl]amino}-2,5,6-trichloro-1,3-dicyanobenzene(1.00g, 2.90 mmol) and dichloromethane (5 ml). After 24 h of mixing atroom temperature the product is recovered on a G-4 filter and thenwashed with dichloromethane. Through vacuum drying on KOH tablets, 1.12g (69%) of product are obtained in the form of a pale yellow powder, mp201-204 ° C.

[0158] IR (KBr): 3420, 3160, 3020, 2940, 2320, 1680, 1640, 1260, 1200,1490, 1400, 1360, 1290, 1240, 1200, 1140, 1110, 1100, 1020, 975, 950,940, 790 and 760 cm⁻¹. ¹H NMR (DMSO-d₆): 1.01-2.66 (8H, m), 4.16-4.25(2H, m), 7.05 (1H, d, J=3.1 Hz), 8.49 (2H, d, J=2.99 Hz) and 8.77 (1H,bs) ppm. ¹³C NMR (DMSO-d₆): 24.28, 24.51, 31.85, 32.02, 53.97, 60.26,97.08, 113.40, 114.64, 119.97, 121.85, 126.80, 127.95, 134.71, 138.14,140.98, 148.66, 121.48, 161.50 ppm. Elem. anal. calcd for C₂₁H₁₄N₆O₅Cl₄(mw 572.18): C, 44.07%; H, 2.46%; N, 14.69%. Found: C, 44.31%; H, 2.87%;N, 14.65%.

EXAMPLE 10N-[(1R,2R)-2-(2,3,5-Trichloro)-4,6dicyanoaniline)-1,2-diphenylethyl]-4-chloro-3,5-dinitrobenzamide

[0159] This selector is prepared as described in Examples 8 and 9, withthe difference that (1R,2R) 1,2-diphenylethane-1,2-diamine is used.

EXAMPLE 11 N-((2S,1R)-2-Hydroxy-indanyl)-(4chloro-3,5dinitrophenyl)carboxyamide

[0160] To the solution of 4-chloro-3,5-dinitrobenzoic acid (0.500 g;2.02 mmol) and EEDQ (0.501 g; 2.02 mmol) in anhydrous tetrahydrofurane(12 ml), a solution of (1S,2R)-(−)-cis-1-amino-2-indanol (0.302 g; 3.38mmol) in anhydrous tetrahydrofurane (12 ml) is added. The mixture ismixed for 16 h at room temperature and is then dry evaporated. The dryresidue is suspended in dichloromethane (20 ml), the solid product isrecovered on a GA4 filter and washed with dichloromethane. The productis dried at 50° C. for 4 h, 0.59 g (77%) of yellowish powder areobtained, m.p. 218-219° C.

[0161] IR (KBr): 3240, 3050, 2880, 1630, 1220, 1340, 1280, 1050, 960,900 and 730 cm⁻¹. ¹H NMR (DMSO-d₆): 2.87 (1H, d, J=16.1 Hz), 3.10 (1H,dd, J=16.1, 7.0 Hz), 4.23 (1H, bs), 4.54 (1H, s), 5.40-5.51 (1H, m),7.11-2.26 (4H, m), 8.92 (2H, s), and 9.12 (1H, d, J=8.6 Hz) ppm. ¹³C NMR(DMSO-d₆): 39.88, 58.36, 72.26, 121.08, 124.75, 124.95, 126.40, 127.72,127.84, 135.44, 140.93, 141.33, 148.67, 162.54 ppm. Elem. anal. calcd.for C₁₆H₁₂O₆N₃Cl (mw 377.7342): C, 50.87%; H, 3.20%; N, 11.12%. Found:C, 50.94; H, 3.28; and N, 11.08%.

EXAMPLE 12N-((1R)-1-Ethyl-2-hydroxyethyl)-(4chloro-3,5-dinitrophenyl)carboxyamide,N-[(1R)-2-Hydroxy-1-(methylethyl)ethyl](4chloro-3,5-dinitrophenyl)carboxyamide,N-((1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl)(4-chloro-3,5dinitrophenyl)-carboxyamide

[0162] These chiral selectors are prepared from chiral amino alcoholsaccording to the method of Example 11.

Example 13 Chiral Stationary Phase CSP-I

[0163] A mixture of the chiral selector of Example 1 (0.60 g, 1.50 mmol)and Nucleosil 100-5NH₂ (3.0 g; C 3.49%, N 1.36%) in DMF (12 ml) is mixedfor 24 h at room temperature. The chiral stationary phase obtained isrecovered on a G-4 filter, washed with DMF and MeOH, and dried at 50° C.for 6 h. 3.33 g of product are obtained. Elem. anal., Found: C, 7.41; H,2.76; N, 2.23%. 1.0 g of chiral stationary phase contains c. 0.21 mmolof bound selector, based on the percentage of C.

EXAMPLE 14 Chiral Stationary Phase CSP-II

[0164] The chiral stationary phase CSP-II is prepared from the chiralselector of Example 2 (0.599 g, 1.50 mmol) and Nucleosil 100-5NH₂ (3.0g) according to the procedure of Example 13. 3.34 g of product areobtained; elem. anal., Found: C, 7.62; H, 2.34; N, 1.97%. 1.0 g ofCSP-II contains c. 0.16 mmol of bound selector, based on the percentageof C.

EXAMPLE 15 Chiral Stationary Phase CSP-III

[0165] The chiral stationary phase CSP-III is prepared from the chiralselector of Example 3 (0.53 g, 1.50 mmol) and Nucleosil 100-5NH₂ (3.0 g)according to the procedure of Example 13. 3.29 g of product areobtained; elem. anal., Found: C, 7.41; H, 2.81; N, 2.25%. 1.0 g ofchiral stationary phase IIII contains c. 0.21 mmol of bound selector,based on the percentage of C.

EXAMPLE 16 Chiral Stationary Phases CSP-IV and CSP-V

[0166] These stationary phases are prepared from the chiral selectors ofExample 4 with the method of Example 13.

EXAMPLE 17 Chiral stationary phase CSP-VI

[0167] The chiral stationary phase CSP-VI is prepared from the chiralselector obtained in Example 6 (0.631 g, 1.50 mmol) and Nucleosil100-5NH₂ (3.0 g) according to the procedure of Example 13. 3.24 g ofproduct are obtained; elem. anal., Found: C, 7.26; H, 1.42; N, 1.61%.1.0 g of CSP-VI contains ca. 0.22 mmol of bound selector, based on thepercentage of C.

EXAMPLE 18 Chiral Stationary Phases CSP-VII and CSP-VIII

[0168] These stationary phases are prepared from the chiral selectors ofExample 7 according to the method of Example 17.

EXAMPLE 19 Chiral Stationary Phase CSP-X

[0169] A mixture of 4-chloro-3,5-dinitrobenzoic acid (0.612 g, 2.49mmol), EEDQ (0.617 g, 2.49 mmol) and silica gel Nucleosil 100-5NH₂(2.572 g) in anhydrous tetrahydrofurane (12 ml) is mixed for 18 h atroom temperature. The modified silica gel is recovered on a G-4 filter,washed with tetrahydrofurane and methanol, and dried at 70° C. for 4 h.The material (2.78 g) is suspended in dichloromethane (12 ml) thenethylenediamine (3 ml) is added. The suspension is mixed for 1 h at roomtemperature and the product is recovered on a GA filter. The modifiedsilica thus obtained is washed with dichloromethane and methanol anddried at 70° C. for 4 h. A mixture of the material (2.800 g),N-(3,5-dinitrobenzoyl)-D-phenylglycine (0.464 g, 1.34 mmol) and EEDQ(0.332 g, 1.34 mmol) in anhydrous tetrahydrofurane (10 ml) is mixed for24 h at room temperature. The chiral stationary phase is recovered on aG-4 filter, washed with tetrahydrofurane and methanol and dried at 70°C. for 4 h. 2.98 g of product are obtained; elem. anal., Found: C,11.14%; H, 1.44%, N, 2.99%. 1.0 g of stationary phase contains ca. 0.28mmol of bound selector, based on the percentage of C.

EXAMPLE 20 Chiral Stationary Phases CSP-IX and CSP-XI

[0170] These stationary phases are prepared fromN-(3,5-dinitrobenzoyl)-L-alanine and N-(3,5-dinitrobenzoyl)-L-leucinewith the method of Example 19.

EXAMPLE 21 Chiral Stationary Phase CSP-XII

[0171] The chiral stationary phase CSP-XII is prepared from the chiralselector of Example 9 (0.858 g, 1.50 mmol) and Nucleosil 100-5NH₂ (3.0g) according to Example 13. 3.30 g of product are obtained; elem. anal.,Found: C, 7.28; H, 1.95; N, 2.55; Cl, 2.84%. 1.0 g of chiral stationaryphase contains ca. 0.27 mmol of bound selector, based on the percentageof C.

EXAMPLE 22 Chiral Stationary Phase CSP-XIII

[0172] This stationary phase is prepared as described in Example 21,with the difference that the chiral selector of Example 10 is used.

EXAMPLE 23 Chiral Stationary Phase CSP-XIV

[0173] The chiral stationary phase CSP-XIV is prepared from the chiralselector of Example 11 (0.566 g, 1.50 mmol) and Nucleosil 100-5NH₂ (3.0g) according to Example 13. 3.26 g of product are obtained; elem. anal.,Found: C 6.90, H 1.23, N 1.57%. 1.0 g of chiral stationary phasecontains ca. 0.21 mmol of bound selector, based on the percentage of C.

EXAMPLE 24 Chiral Stationary Phases CSP-XV-CSP-XIX

[0174] These stationary phases are prepared from the chiral selectors ofExample 12 according to the method of Example 23.

[0175] Examples of separation of racemic mixtures with the chiralstationary phases of the invention (examples 25-36)

[0176] General procedure applied in Examples 25-36 for the separation ofracemic mixtures using HPLC columns containing the chiral stationaryphases of the invention.

[0177] A Knauer WellChrom. Maxi-Star K-1000 pump is used (Knauer GmbH,Berlin, Germany) with a Knauer HPLC 6-port-valve injector and a 20 μlloop. The measurement is taken at 254 nm with a Knauer WellChrom K-2500detector. Integration of the peaks of the chromatograms is performedwith the BDS software package (Barspec Ltd., Rehovot, Israel). Thepacking of the HPLC columns, acquired from Max Stevenson (Berlin,Germany, dimensions 150×4.6 mm) is performed with the “slurry” techniqueusing a pneumatic pump for Knauer HPLC. The n-hexane, 2-propanol,dichloromethane and other solvents used for HPLC with analytical purityof J. T. Baker, are redistilled before use. The dead volume of thecolumn was measured with 1,3,5-tri-tert-butylbenzene. The structures ofthe tested racemi are shown in FIG. 2.

EXAMPLE 25

[0178] Separation of Racemic Mixtures of Derivatives of Amino Acids(R-17-R-24) with CSP-II, CSP XIV, CSP VI

[0179] The chromatographic columns for HPLC are filled with the CSP anddifferent racemic mixtures of derivatives of amino acids are separated.The mobile phase utilized is 20% of 2-propanol in n-hexane with a flowof 1.0 mlmin. The two enantiomers of each mixture are resolved and thechromatogram has two separate symmetrical peaks with separation factor(α) and resolution factor (R_(s)) shown in Table 1. TABLE 1 CSP II CSPXIV CSP VI α R_(S) α R_(S) α R_(S) R-17 1.36 2.08 1.24 2.41 2.28 12.78R-18 1.62 3.80 1.30 2.57 2.32 13.22 R-19 1.79 4.00 1.26 2.46 3.72 25.28R-20 1.61 3.31 1.29 3.05 2.64 18.22 R-21 1.26 2.33 1.31 3.29 1.88 9.65R-22 1.36 2.83 1.30 3.06 2.84 21.41 R-23 1.59 4.55 1.31 3.22 2.68 10.37R-24 1.41 2.47 1.16 1.62 2.12 9.12

[0180] Representative compounds of derivatives of amino acids aresuccessfully separated by means of different CSP. In particular, thevery good separation of R-19 with CSP-VI is highlighted.

EXAMPLE 26 Separation of Racemic Mixtures of Dihydropyrimidine(R-28-R-32) with CSP-VI, CSP III, CSP XIV

[0181] The chromatographic columns for HPLC are filled with the CSP anddifferent racemic mixtures of drugs used in controlling blood pressureare separated using n-hexane/2-propanoVacetic acid (80:20:1) as a mobilephase at a flow of 1.0 ml/min. The two enantiomers of each mixture areresolved and the chromatogram has two separate symmetrical peaks withseparation factor (α) and resolution factor (R_(s)) shown in Table 2.TABLE 2 CSP VI CSP III CSP XIV α R_(S) α R_(S) α R_(S) R-28 1.20 2.491.10 1.21 1.17 1.32 R-29 1.18 2.18 1.08 1.07 1.09 0.69 R-30 1.25 3.111.13 1.82 1.12 1.11 R-31 1.12 1.98 1.00 0 1.18 1.94 R-32 1.02 nm 1.040.52 1.17 1.82

[0182] Very effective separations were obtained for different racemicmixtures belonging to this class of drugs.

Example 27 Separation of Racemic Mixtures with CSP-II

[0183] The two enantiomers of each mixture are resolved and thechromatogram has two separate symmetrical peaks with separation factor(α), resolution factor (R_(s)) retention time of the enantiomer R1 andR2 (t_(R1), t_(R2)) and capacity factors (k′₁, k′₂) shown in Table 3.The mobile phase utilized is 20% of 2-propanol in n-hexane with a flowof 1.0 ml/min. TABLE 3 t_(R1) t_(R2) k′₁ k′₂ α R_(S) R-12 3.85 4.08 0.530.62 1.17 0.92 R-13 6.42 6.90 1.83 2.04 1.11 1.07 R-14 9.35 9.85 3.123.34 1.07 0.66 R-16 12.78 17.63 4.63 6.76 1.46 4.20

[0184] From these data it can be deduced that the stationary phaseCSP-II allows an excellent separation not only of DNB derivatives ofamino acids, as seen in Example 26, but also of compounds containingother amidic groups.

EXAMPLE 28 Separation of Racemic Mixtures With CSP-III

[0185] The two enantiomers of each mixture are resolved and thechromatogram has two separate symmetrical peaks with separation factor(α), resolution factor (R_(s)) retention time of the enantiomer R1 andR2 (t_(R1), t_(R2)) and capacity factors (k′₁, k′₂) shown in Table 4.The mobile phase utilized is 1% of methanol in n-hexaneldichloromethane(100:30) with a flow of 1.0 ml/min. TABLE 4 T_(R1) t_(R2) k′₁ k′₂ αR_(S) R-6 12.00 16.10 3.64 4.1 1.13 1.38 R-8 7.80 8.05 1.41 1.49 1.100.42^(a) R-9 25.50 26.72 6.89 7.27 1.06 0.76 R-10 6.47 6.63 1.00 1.101.10 0.29^(a) R-12 10.62 11.12 2.29 2.44 1.07 1.00 R-16 48.12 67.0313.89 19.75 1.42 2.70 R-18 18.02 19.50 4.80 5.04 1.10 1.35 R-19 21.0322.12 5.51 5.86 1.06 0.97 R-21 35.97 40.62 10.14 11.58 1.14 2.33 R-2227.02 28.68 7.37 7.88 1.07 1.38 R-23 38.73 41.32 10.88 11.79 1.08 1.36R-25 9.83 11.08 2.04 2.43 1.19 1.67

[0186] From these data it can be deduced that the stationary phaseCSP-III allows the separation of various structurally different racemicmixtures.

EXAMPLE 29 Separation of Racemic Mixtures With CSP-XII

[0187] The two enantiomers of each mixture are resolved and thechromatogram has two separate symmetrical peaks with separation factor(α), resolution factor (R_(s)) retention time of the enantiomer R1 andR2 (t_(R1), t_(R2)) and capacity factors (k′₁, k′₂) shown in Table 5.TABLE 5 t_(R1) t_(R2) K′₁ k′₂ α R_(S) R-3^(a) 17.07 19.05 4.69 5.35 1.141.27 R-5^(b) 27.93 31.12 6.35 7.18 1.13 0.94 R-7^(c) 12.37 18.72 4.125.24 1.27 2.43 R-12^(d) 6.93 7.67 1.31 1.56 1.19 1.27 R-13^(d) 12.6519.35 4.22 5.45 1.29 4.11 R-16^(d) 17.05 20.95 4.68 5.98 1.28 3.79R-17^(d) 9.27 10.12 2.09 2.37 1.13 1.09 R-27^(c) 13.77 16.68 3.59 4.561.27 2.37 R-31^(c) 11.60 12.80 2.87 3.27 1.14 1.07

EXAMPLE 30 Separation of Warfarin (R-3) with CSP-III

[0188] The warfarin (R-3) is successfully separated usingn-hexane/2-propanol/acetic acid (80:20:1) as a mobile phase, at a flowof 1.0 ml/min. The two enantiomers are separated with α=1.24,R_(s)=4.09, t_(R1)=14.12 min. and t_(R2)=16.33 min.

EXAMPLE 31 Separation of 3,5-dinitrobenzoyl-leucine (R-19) With CSP-VI

[0189] The two enantiomers of 3,5-dinitrobenzoyl-leucine are separatedwith t_(R1)=7.18 min. and t_(R2)=25.87 min. usingn-hexane/dichloromethane/methanol (100:30:1) as a mobile phase, at aflow of 2.0 ml/min.

EXAMPLE 32 Separation of Racemic Mixtures of2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (R-5, BINAPO) with CSP-X

[0190] An extraordinary separation of BINAPO (R-5) is obtained withCSP-X using n-hexanel2-propanol (50:50) as a mobile phase, at a flow of2.0 ml/min. The two enantiomers are separated with α=2.37, R_(s)=3.88,t_(R1)=6.0 min. and t_(R2)=11.87 min. This process could be of use alsofor the separation and the analysis of the BINAP catalyst(2,2′-bis(diphenylphosphinil)-1,1′-binaphthalene), a much used catalyst,since BINAP is easily oxidized to BINAPO without racemizing, and BINAPOis also easily reduced again to BINAP

Example 33 Separation of Benzodiazepine (R-7) with CSP-XIV

[0191] The racemic mixture R-7 is separated usingn-hexane/dichloromethane/methanol (100:30:1) as a mobile phase, at aflow of 2.0 ml/min. The two enantiomers are separated with t_(R1) 36.82min. and t_(R2) 43.20 min.

EXAMPLE 34 Separation of R-4 With CSP-XI

[0192] The racemic mixture is separated usingn-hexane/dichloromethane/methanol (100:30:1) as a mobile phase, at aflow of 1.0 ml/min. The two enantiomers are separated with α=1.20,R_(s)=2.35

EXAMPLE 35 Separation of R-1 with CSP-VI and CSP-IX

[0193] The two enantiomers of the mixture are resolved and thechromatogram has two separate symmetrical peaks with separation factor(α), resolution factor (R_(s)) shown in Table 6. TABLE 6 α R_(S)CSP-VI^(a) 1.05 0.49 CSP-IX^(b) 1.05 0.43

Example 36 Separation of R-26 With CSP-XIV

[0194] The racemic mixture is separated using n-hexane/2-propanol (9:1)as a mobile phase, at a flow of 1.0 m/min. The two enantiomers areseparated with α=1.10, R_(s)=1.03. The data shown here highlight thatthe chiral stationary phases of the invention allow the efficientseparation of a wide range of racemic analytes. Of particularsignificance, among the analytes separated, are those denoted by R-1,R-5 (BINAPO), R-25, R-26, R-28, R-29, R-30, R-31, R-32 (see FIG. 2):such analytes were not separable either by commercial stationary phasesbased on 3,5-DNB derivatives (in particular, by the derivative ofphenylglycine, Chiral-2, Macherey Nagel)), or by those based onderivatives of 1,3-dicyanobenzene. Therefore, the CSP according to theinvention, besides having a broad general spectrum of use, have for thefirst time allowed the separation of a high number of analytes not yetseparable by means of known CSP.

1. Chiral stationary phase represented by the structure (I):

in which: P is: (i): a chiral group in an enantiomerically pure form,chosen between: —(CH₂)_(n)NHCOCH(R¹)NH(R²) where: n ranges from 2 to 4,R¹ is C₁-C₅ linear or branched alkyl, aryl; R² is COAr or Ar, where Aris an aryl or alkylaryl group, optionally substituted with one or moregroups chosen among: NO₂, CN, Cl, CH₃, OCH₃ —COCH(R¹)NH(R²) where: R¹andR² are defined as above; (ii) or P is a spacer group covalently bound toa solid support for chromatography Q is: (i) a chiral group in anenantiomerically pure form, chosen among: —CHR¹⁰R¹¹ where: R¹⁰ is H,C₁-C₅ linear or branched alkyl; R¹¹ is cycloalkyl, arylalkyl, aryl,optionally substituted with one or more groups chosen among: NO₂, CN,Cl, CH₃, OCH₃ —CH(R¹³)CONH(R¹⁴) where: R¹³ is H, C₁-C₅ linear orbranched alkyl, aryl, optionally substituted with NO₂, CN, Cl, CH₃,OCH₃; R¹⁴ is alkylaryl, aryl, optionally substituted with one or moregroups chosen among: NO₂, CN, Cl, CH₃, OCH₃ —CH(R³)CH(R⁴)(NHR⁵) where:R³ and R⁴ independently of each other are C₁-C₅ linear or branchedalkyl, aryl, alkylaryl, optionally substituted with NO₂, CN, Cl, CH₃,OCH₃, or R³ forms with R⁴ and with the carbon atoms bound to R³ and R⁴ a5-6 term ring; R⁵ is an aryl, benzoyl group, optionally substituted withone or more groups chosen among: NO₂, CN, Cl, CH_(3,) OCH₃.—CH[CH(R¹⁷)(R⁷)][R⁹] where: R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH,R⁷ is H, C₁-C₅ linear or branched alkyl, or R⁷ forms with R⁸ and withthe carbon atoms bound to R⁷ and R⁸ a 5-6 term ring; R⁸ is H, C₁-C₅linear or branched alkyl, phenyl, or R⁸ forms with R⁶ and with thecarbon atoms bound to R⁸ and R⁶ a 5-6 term ring optionally of aromaticnature; R⁶ is H, C₁-C₅ linear or branched alkyl, hydroxyl; (ii) or Q isa spacer group covalently bound to a solid support for chromatography,and in which the aforesaid formula (I) always contains one chiral groupand one spacer group bound to a solid support for chromatography, asdefined above.
 2. Stationary phase according to claim 1, where P is achiral group and Q is a spacer group bound to a solid support forchromatography.
 3. Stationary phase according to any one of the claims1-2, where the alkylaryl groups are represented by the benzyl group, 4.Stationary phase according to any one of the claims 1-3, where the arylgroups are represented by phenyl, naphthyl,2,5,6-trichloro-1,3-dicyanophenyl or 4,5,6-trichloro-1,3-dicyanophenyl.5. Stationary phase according to claim 1, where P is—(CH₂)_(n)NHCOCH(R¹)NH(R²), n is 2; R¹ is methyl, isopropyl, isobutyl,phenyl, benzyl; R² is 3,5-dinitrobenzoyl,2,5,6-trichloro-1,3-dicyanophenyl, 4,5,6-trichloro-1,3-dicyanophenyl. 6.Stationary phase according to claim 1, where Q is —CHR¹⁰R¹¹, R¹⁰ ismethyl; R¹¹ is cyclohexyl, phenyl, naphthyl, anthranyl,2,5,6-trichloro-1,3-dicyanophenyl, 4,5,6-trichloro,1,3-dicyanophenyl,para-nitrophenyl.
 7. Stationary phase according to claim 1, where Q is—CH(R¹³)CONH(R¹⁴), R¹³ is methyl, phenyl, isobutyl; R¹⁴ is phenyl,dimethylphenyl;
 8. Stationary phase according to claim 1, where Q is—CH(R³)CH(R⁴)(NHR⁵), R³ and R⁴ are phenyl or R³ forms with R⁴ and withthe carbon atoms bound to R³ and R⁴ a 6-term ring; R⁵ is4,5,6-trichloro-1,3-dicyanophenyl, 2,4,6-trichloro-1,3-dicyanophenyl; 9.Stationary phase according to claim 1, where Q is CH[CH(R¹⁷)(R⁷)][R⁹],in which: R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH; R⁷ is H, or R⁷forms with R⁸ and with the carbon atoms bound to R⁷ and R⁸ a 5-termring, or R⁸ is H, methyl, phenyl, or R⁸ forms with R⁶ and with thecarbon atoms bound to R⁶ a 5-6 term ring of aromatic nature, R⁶ ismethyl, hydroxyl.
 10. Stationary phase according to any one of theclaims 1-9, where the spacer group covalently bound to a solid supportfor chromatography has the formula —(CH₂)_(n)—Si—(R¹²)(R¹⁶)—O—R¹⁵, wheren ranges from 1 to 10; R¹² and R¹⁶ are C₁-C₄ alkyl, C₁-C₄ alkoxy, O—R¹⁵,and R¹⁵ represents the solid support for chromatography.
 11. Stationaryphase according to claim 10, where R¹² is the same as R¹⁶ and representsethoxy, n is 3, and R¹⁵ is a silyl residue of silica, or R¹² is ethoxyand R¹⁶ is —OR¹⁵, and R¹⁵ is a silyl residue of silica.
 12. Stationaryphase according to any one of the claims 1-11, where the solid supportis of inorganic nature.
 13. Stationary phase according to claims 1-12,where the solid support is chosen among silica gel, alumina, kaolin,titanium oxide, magnesium oxide, silicate, synthetic polymers. 14.Process for the production of the chiral stationary phases described inthe claims 1-13, including the following steps, applicable in any order:introduction of a chiral group (P or Q) on the ring of a4-halo-3,5dinitro-benzoic acid; introduction of a spacer group (Q or P)on the ring of the 4-halo-3,5-dinitro-benzoic acid; formation of acovalent bond between the spacer group and the solid support. 15.Process according to claim 14, wherein said 4-halo is 4-chloro. 16.Process according to claims 14-15, in which the spacer group is made toreact first with the solid support and then with4-chloro-3,5-dinitro-benzoic acid.
 17. Chiral selector for theproduction of the stationary phases described in the claims 1-13, saidselector having the formula (Ia) or (Ib)

in which: P is a chiral group in an enantiomerically pure form, chosenbetween: —(CH₂)_(n)NHCOCH(R¹)NH(R²) where: n ranges form 2 to 4, R¹ isC₁-C₅ linear or branched alkyl, aryl; R² is COAr or Ar, where Ar is anaryl or alkylaryl group, optionally substituted with one or more groupschosen among: NO₂, CN, Cl, CH₃, OCH₃ —COCH(R¹)NH(R²) where: R¹ and R²are defined as above; Hal is halogen, Q is chosen among: a chiral groupin an enantiomerically pure form, of formula: —CHR¹⁰R¹¹ where: R¹⁰ is H,C₁-C₅ linear or branched alkyl; R¹¹ is cycloalkyl, arylalkyl, aryl,optionally substituted with one or more groups chosen among: NO₂, CN,Cl, CH₃, OCH₃. —CH(R¹³)CONH(R¹⁴) where: R¹³ is H, C₁-C₅ linear orbranched alkyl, aryl, optionally substituted with NO₂, CN, Cl, CH₃,OCH₃, R¹⁴ is alkylaryl, aryl, optionally substituted with one or moregroups chosen among: NO₂, CN, Cl, CH₃, OCH₃. —CH(R³)CH(R⁴)(NHR⁵) where:R³ and R⁴ independently of each other are C₁-C₅ linear or branchedalkyl, aryl, alkylaryl, optionally substituted with NO₂, CN, Cl, CH₃,OCH₃, or R³ forms with R⁴ and with the carbon atoms bound to R³ and R⁴ a5-6 term ring; R⁵ is an aryl, benzoyl group, optionally substituted withone or more groups chosen among: NO₂, CN, Cl, CH₃, OCH₃.—CH[CH(R¹⁷)(R⁷)][R⁹] where: R⁹ is OH, —CHR⁸R⁶ or phenyl; R¹⁷ is H or OH;R⁷ is H, C₁-C₅ linear or branched alkyl, or R⁷ forms with R⁸ and withthe carbon atoms bound to R⁷ and R⁸ a 5-6 term ring; R⁸ is H, C₁-C₅linear or branched alkyl, phenyl, or R⁸ forms with R⁶ and with thecarbon atoms bound to R⁸ and R⁶ a 5-6 term ring optionally of aromaticnature; R⁶ is H, C₁-C₅ linear or branched alkyl, hydroxyl.
 18. Chiralselector. according to claim 17, formula (Ia) where Pis—(CH₂)_(n)NHCOCH(R¹)NH(R²), n is 2; R¹ is methyl, isopropyl, isobutyl,phenyl, benzyl; R² is 3,5-dinitrobenzoyl,2,5,6-trichloro-1,3-dicyanophenyl, 4,5,6-trichloro-1,3-dicyanophenyl.19. Chiral selector according to claim 17, formula (Ib), where Q is—CHR¹⁰R¹¹, R¹⁰ is methyl; R¹¹ is cyclohexyl, phenyl, naphthyl,anthranyl, 2,5,6-trichloro-1,3-dicyanophenyl,4,5,6-trichloro-1,3-dicyanophenyl, para-nitrophenyl.
 20. Chiral selectoraccording to claim 17, formula (Ib), where Q is —CH(R¹³)CONH(R¹⁴), R¹³is methyl, phenyl, isobutyl; R¹⁴ is phenyl, dimethylphenyl.
 21. Chiralselector according to claim 17, formula (Ib), where Q is—CH(R³)CH(R⁴)(NHR⁵), R³ and R⁴ are phenyl or R³ forms with R⁴ and withthe carbon atoms bound to R³ and R⁴ a 6-terrn ring; R⁵ is4,5,6-trichloro-1,3-dicyanophenyl, 2,4,6-trichloro-1 ,3-dicyanophenyl;22. Chiral selector according to claim 17, formula (Ib), where: Q is—CH[CH(OH)R⁷][R⁹], R⁹ is CHR⁸R⁶, phenyl; R⁷ is H, or R⁷ forms with R⁸and with the carbon atoms bound to R⁷ and R⁸ a 5-term ring, or R⁸ is H,methyl, phenyl, or R⁸ forms with R⁶ and with the carbon atoms bound toR⁶ a 5-6 term ring of aromatic nature, R⁶ is methyl, hydroxyl. 23.Chiral selector according to claim 17, chosen between:N-(1R)(1-phenylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide,N-(1R)(1-Naphthylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide,N-(1R)(9-Anthranylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide,N-(1R)-(1-Cyclohexylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide,N-(1R)-[1-(4-Nitrophenyl)ethyl]-(4-chloro-3,5-dinitrophenyl)carboxyamide,(2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5dinitrophenyl)carbonylamino]propanamide,(2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-2-isobutylacetamide,(2R)-N-(3,5-Dimethylphenyl)-2-[(4-chloro-3,5-dinitrophenyl)carbonylamino]-2-phenylacetamide,N-[(1R,2R)-2-[(3,5,6-Trichloro)-2,4-dicyanophenyl)amino]cyclohexyl}-4-chloro-3,5-dinitrophenyl)carboxyamide,N-[-(1R,2R)-2-(2,3,5-Trichloro)-4,6-dicyanoaniline)-1,2-diphenylethyl]4-chloro-3,5-dinitrobenzamide,N-((2S, 1R)-2-Hydroxy-indanyl)-(4-chloro-3,5-dinitraphenyl)carboxyamide,N-((1R)-1-Ethyl-2-hydroxyethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide,N-[(1R)-2-Hydroxy-1-(methylethyl)ethyl](4-chloro-3,5-dinitrophenyl)carboxyamide,N-((1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl)(4-chloro-3,5-dinitrophenyl)carboxyamide.
 24. Use of the chiral stationary phases described in anyone of the claims 1-13 in the analytical or preparative chromatographicseparation of enantiomers or mixtures of racemi.
 25. Use according toclaim 24, where the separation is carried out by liquid chromatography,HPLC, SMBC, SCFC.